Apolipoprotein(a) polymorphism predicts the increase of Lp(a) by pravastatin in patients with familial hypercholesterolaemia treated with bile acid sequestration

Abstract. HMG-CoA reductase inhibitors effectively reduce the concentration of low density lipoproteins (LDL) in plasma. Lipoprotein(a) [Lp(a)] may be as atherogenic as LDL. A few studies, only one of which was placebo controlled, suggest that the HMG CoA reductase inhibitors either do not affect Lp(a) or they increase Lp(a). The response of Lp(a) to HMG-CoA reductase inhibition has not been related to apolipo-protein(a) phenotypes in previous studies. We conducted a double-blind, placebo controlled study of pravastatin in 51 patients with familial hypercholester-olemia (FH) ( n = 43) or probable FH ( n = 8). All patients had LDL-cholesterol concentrations above 4.1 mmol 1^-1 despite treatment with diet and bile acid sequestration. In patients assigned to pravastatin ( n = 34), the mean concentrations of total cholesterol and LDL cholesterol fell significantly ( P< 0.01) when compared to placebo. Lp(a) increased ( P< 0.01) from a mean (±SD) of 33.6 ± 40.8 mgdl^-1 to 411 ± 46.1 mg dl^-1 on pravastatin but was unchanged during placebo treatment. The percentage increase in Lp(a) was the same in patients with different apo(a) phenotypes, and hence the absolute increase in Lp(a) was greatest in patients with the low molecular weight apo(a) phenotypes.     

Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model

Proliferation of smooth muscle cells (SMCs) plays an important role in vascular pathobiology by being involved in the development of coronary atherosclerosis and restenosis. Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase have shown antiproliferative properties on different cell types. We have assessed the relative effectiveness of three HMG-CoA reductase inhibitors (compactin, lovastatin and pravastatin) in blocking serum-induced replication of human and porcine SMCs. No effects were seen on DNA synthesis in porcine or human SMCs at the reported therapeutic lipid-lowering concentrations. The effectiveness of statins in blocking SMC proliferation was similar in both species; the IC₅₀ values for porcine cells were 12.2μmolL⁻¹, 12.6μmolL⁻¹ and 1.16mmolL⁻¹ for lovastatin, compactin and pravastatin respectively. Inhibition of SMC proliferation was reversed by addition of mevalonate but not by low-density lipoprotein (LDL)-cholesterol. Statins showed high antiproliferative efficiency against purified growth factors involved in human restenosis (1nmolL⁻¹ platelet-derived growth factor (PDGF), 1nmolL⁻¹ epidermal growth factor (EGF), 10UmL⁻¹α-thrombin). The porcine model seems to be a suitable system, closely resembling the human model, for assaying in vivo new strategies, formulations and delivery systems targeted to the mevalonate pathway to inhibit local SMC response to percutaneous transluminal coronary angioplasty.     

Lipid peroxidation and susceptibility of low-density lipoprotein to in vitro oxidation in hyperhomocysteinaemia

Abstract. The pathobiochemical mechanism of arteriosclerosis in hyperhomocysteinaemia has not yet been elucidated. In vitro studies have shown that the cytotoxic properties of homocysteine can be ascribed to its generation of reactive oxygen species. We studied lipid peroxidation, both in vivo and in vitro , in 10 homozygous cystathionine synthase-deficient (CSD) patients and in a control group of 10 healthy subjects of comparable age and sex. The susceptibility of low-density lipoprotein (LDL) from hyperhomo-cysteinaemic patients to oxidation was determined in vitro by continuously measuring the conjugated diene production induced by incubation with copper ions. Oxidation resistance (expressed as lag time), maximal oxidation rate, and extent of oxidation (expressed as total diene production) of LDL from CSD patients were not significantly different from those of LDL from controls. Furthermore, the time needed to reach maximal diene production, i.e. t(max), was similar for LDL from patients and controls. In addition, the vitamin E concentrations in LDL of CSD patients and controls were similar. The mean concentration (± SD) of plasma thiobarbituric acid reactive substances (TBARS), an indicator of in vivo lipid peroxidation, was 2.2 ± 0.7 μmol L^-1 in CSD patients, a lower value than that measured in the matched controls (50± 2.0 μmol L^-1). Investigation of in vivo and in vitro parameters of lipid peroxidation shows that the increased risk of arteriosclerosis in hyperhomocysteinaemia is unlikely to be due to increased lipid peroxidation.     

Simvastatin and pravastatin equally improve flow-mediated dilation in males with hypercholesterolemia

BACKGROUND: Both simvastatin and pravastatin have been shown to improve endothelial function in patients with hypercholesterolemia. To our knowledge there has been no comparative study of these two HMG-CoA reductase inhibitors on endothelial dysfunction measured by flow-mediated dilation of the brachial artery in patients with hypercholesterolemia. METHODS: Fourteen middle-aged males with hypercholesterolemia (means +/- SD: total cholesterol 7.03 +/- 0.88 mmol/l, LDL cholesterol 5.02 +/- 0.63 mmol/l, HDL cholesterol 1.3 +/- 0.38 mmol/l and triglycerides 1.47 +/- 0.26 mmol/l) were randomised, after a 6 weeks' run-in phase with AHA step I diet treatment, to 12 weeks' treatment either with simvastatin or pravastatin. Both statins were given in a daily dose of 10 mg for 6 weeks, which was increased to 20 mg daily in patients who did not achieve an LDL-cholesterol goal of < 3.4 mmol/l. Endothelial dysfunction was measured as flow-mediated brachial artery dilation (FMD) using high resolution ultrasound. RESULTS: There were no significant differences between the drugs in reduction of total cholesterol, LDL cholesterol and triglycerides, or elevation of HDL cholesterol. FMD increased in the simvastatin group from 6.8 +/- 3.2 to 12.3 +/- 2.9% (p < 0.03) and in the pravastatin group from 6.3 +/- 4.8 to 13.3 +/- 4.7% (p = 0.001). The improvement in FMD was the same in both groups (p = 0.64) and did not correlate with changes of the lipid parameters measured. CONCLUSIONS: Both simvastatin and pravastatin reduce endothelial dysfunction to the same degree in patients with hypercholesterolemia, independently of changes in lipid parameters.     

Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications

Abstract. We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day^-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% ( P = 0.002), triglycerides by 27% ( P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% ( P = 0.002); high-density lipoprotein cholesterol increased by 17% ( P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of l-[¹³C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a mono-exponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day^-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007mgkg^-1day^-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0)mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration ( P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol. This effect does not appear to be directly related to the inhibition of cholesterol synthesis and may be due to decreased hepatic delivery of cholesterol esters via the LDL receptor-independent pathway, but these mechanisms require further investigation.     

Treatment of childhood hypercholesterolemia with HMG-CoA reductase inhibitors

OBJECTIVE: To describe the development of coronary artery disease in childhood and review the available literature regarding the safety and efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) when used during childhood and adolescence. DATA SOURCES: A MEDLINE search was performed for the period of January 1966 through January 1999 using the key terms hypercholesterolemia, hyperlipidemia, and hydroxymethylglutaryl CoA reductase inhibitors. The search was further limited to English language, human study group, and all-child (0-18 y) age group. STUDY SELECTION AND DATA EXTRACTION: All clinical studies involving the use of HMG-CoA reductase inhibitors exclusively during childhood or adolescence were evaluated. DATA SYNTHESIS: A mean low-density lipoprotein cholesterol (LDL-C) concentration reduction of 25% can be obtained in children and adolescents treated with lovastatin, pravastatin, or simvastatin along with a lipid-lowering diet. The statins are generally well-tolerated in children and adolescents. Transient, asymptomatic elevations in creatine phosphokinase and hepatic transaminase concentrations have been reported in a small number of the children evaluated. Current data do not suggest any adverse effects on normal growth and sexual development in male adolescents, but formal evaluations have not been performed in female adolescents. CONCLUSIONS: The addition of the HMG-CoA reductase inhibitors lovastatin, pravastatin, or simvastatin to diet therapy in children > or =10 years of age may be effective when diet therapy alone has failed to obtain the recommended maximum LDL-C concentration of 130 mg/dL. The use of statins during childhood and adolescence is generally safe, but large, long-term studies should be performed before statins are routinely prescribed to children with elevated cholesterol or lipoprotein concentrations.     

Effects of cyclooxygenase inhibitors, prostaglandins F2α and I2, on isolated coeliac and basilar arteries of alloxan-diabetic dogs

Abstract. The effects of prostaglandin synthetase inhibitors PGF_2α and PGI₂ on the tone of isolated basilar and coeliac arteries were studied in healthy and alloxan-diabetic dogs. PGF_2α (1 μmol l^-1) produced a significantly higher tone in diabetic basilar arteries (1·15 ± 0·16 mN) than in normal cerebral vessels (0·7 + 0·10 mN). By contrast, the contractile responses of normal and diabetic coeliac arteries to PGF_2α did not differ. The cyclooxygenase inhibitors indomethacin (3 μmol l^-1) and suprofen (0·58 μmol l^-1) potentiated the PGF_2α-evoked contractions in all of the vessels studied. The percent potentiation was greater (50–60%) in the basilar arteries from alloxan-treated dogs than in normal basilar vessels (22–30%). There was not such a difference between diabetic and normal coeliac arteries. Prostacyclin produced a concentration-related relaxation in the presence of indomethacin or indomethacin + PGF_2α. The relaxant potencies of PGI₂ were similar in the vessels from metabolically healthy and diabetic dogs. The IC₅₀ values for PGI₂ were 11·6 ± 1·3 and 11·8 ± 1·8 nmol l^-1 in normal and diabetic basilar arteries, respectively; they were 25·4 ± 3·2 and 26·2 ± 3·9 nmol l^-1 in control and alloxan-treated coeliac vessels. These results indicate that normal and diabetic vessels may have differential reactivity to cyclooxygenase inhibitors, this difference being dependent on the vascular region.     

The effect of probucol and vitamin E treatment on the oxidation of low-density lipoprotein and forearm vascular responses in humans

Abstract This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low-density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double-blind parallel group study, 24 hypercholesterolaemic patients, already on treatment with simvastatin (20mg day^-1), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400 IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7·00 mmol l^-1. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobarbituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDL-and LDL-cholesterol levels and increased the QT interval. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and N^G-monomethyl-L-arginine, were not significantly changed by antioxidant treatment. Probucol has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.     

No evidence for feedback inhibition of hepatic apolipoprotein B (apo B) production after extracorporeal low density lipoprotein precipitation as determined by [I-13C]leucine infusion in normal volunteers

Abstract. To determine the impact of an acute reduction of the circulating mass of apolipoprotein B (apo B) on apo B metabolism we studied six healthy male volunteers before (day 0), 1 day after (day 2), and 7 days after (day 8) an LDL apheresis treatment which reduced apo B mass by 59%. Appearance of newly synthesized apo B in plasma VLDL and LDL was studied using a primed-constant infusion of [I-¹³C]-leucine. VLDL apo B pool size and fractional VLDL apo B production rate calculated using a one-compartment model were similar on all 3 study days. Absolute VLDL apo B production was not statistically different throughout the study (19.7±12.3, 19.5 ± 7.5, 29.1 ± 17.7 mg kg^-1 day^-1). LDL apo B fractional production rate was increased on day 2 (0.38 ± 0.17, 0.68±0.08, 0.37±0.06 pools day^-1on days 0, 2, and 8; P <0.01). Absolute LDL apo B production, however, remained constant throughout the study (10.8 ± 3.3, 11.0±1.9, 10.8 ± 3.1 mg kg^-1 day^-1). We conclude that in healthy male volunteers acute reduction of the circulating apo B mass by LDL apheresis does not affect apo B metabolism significantly.     

CHANGES IN PLATELET FREE Ca2+ CONCENTRATION AFTER CHRONIC DIGOXIN TREATMENT

Summary— Cell Na+ and Ca²⁺ concentrations control each other by various mechanisms. In excitable cells from various origins, Ca²⁺ extrusion from the cell and its entry are dependent for a large part on the activity of the Na+, Ca²⁺-countertransport system. Cytosolic free Ca²⁺ concentration is also controlled by the Na+–H+ exchange activity. To analyze the changes in cytosolic Ca²⁺ concentration accompanying the reduction of the membrane Na+ gradient, cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) was measured by fluorescent dyes in platelets and erythrocytes from healthy subjects, before and during digoxin treatment (0.25 mg/day for 6 days). [Ca²⁺]_i was increased in platelets from 169±30 to 321±61 nmol/l ( n = 7, P <0.02) and unchanged in erythrocytes (121±6 and 104±7 nmol/l). This increase in platelet [Ca²⁺]_i was not accompanied by a change in serotonin content (5.43±0.67 vs 5.49±0.61 10⁻⁷ mol per 10¹¹ cells) and could not be reproduced by in vitro addition of 10⁻⁴ mol/l ouabain (198±33 vs 186±73 nmol/l). The enhanced [Ca²⁺]_i in platelets is thus not a short-term consequence of a reduced membrane Na+ gradient, but reflects either the overload of intracellular Ca²⁺ stores or an enhanced in vivo stimulation by hormones or neurotransmitters.     

Electrokinetic properties of human cryopreserved platelets

SUMMARY. A method for the cryopreservation of human platelets with glycerol/glucose is described which was a simplified modification of the method of Dayian and Pert (1979). The effect of cryoinjury of the platelet surface membrane was investigated by studying the surface electrokinetic properties of the platelet. A significant increase in platelet electrophoretic mobility was found after cryopreservation. The fresh platelets had a mean electrophoretic mobility of 1.04 ± 0.05 μm s^-1 V^-1 cm^-1 and cryopreserved platelets 1.18 ± 0.05 μm s^-1 V^-1 cm^-1, P < 0.05. However, the total platelet sialic acid of fresh platelets was 62.5 ± 5.6 nmol 10^-9 platelets compared to 47.2 ± 4.6 nmol 10^-9 platelets after cryopreservation, P < 0.001. Similarly, the neuraminidase-labile sialic acid was 26.4 ± 4.3 nmol 10^-9 platelets for fresh platelets and 17.6 ± 4.0 nmol 10^-9 platelets after cryopreservation, P < 0.001.
Using polyacrylamide gel electrophoresis with Western blotting, we showed a reduction in the platelet glycoprotein Gp Ib after cryopreservation, this was confirmed by using crossed immunoelectrophoresis. Electron microscopy revealed a significant change in platelet morphology after the cryopreservation procedure with disruption of the platelet membrane and also platelet shape change. These features may explain the changes in platelet electrokinetic properties.     

Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria

Abstract. Two enzymes of the haem biosynthetic pathway were investigated in patients with variegate porphyria. Protoporphyrinogen oxidase in cultures of Epstein-Barr virus transformed lymphoblasts from twenty-seven patients showed a mean maximal velocity ( V _max) of 0·39 ± 0·08⁺ nmol of protoporphyrin mg protein^-1 h^-1, a 52% reduction ( P < 0·001) from a non-porphyric control group (0·82 ± 0·10). K _m values (1·00 ± 0·27 μ M) did not differ significantly ( P > 0·05) from control values in any of the patients. The mean V _max of porphobilinogen deaminase in the cultures was 1·50 ± 0·18 nmol of uroporphyrin mg protein^-1 min^-1, a 24% reduction ( P < 0·001) from controls (1·94 ± 0·14). Mean porphobilinogen deaminase activity in the erythrocytes of twenty-one patients with variegate porphyria was 8·37 ± 1·99 nmol of uroporphyrin 1 erythrocytes^-1 s^-1, a 28% reduction ( P < 0·001) from normal (11·98 ± 2·11). The reduced activities of these two enzymes comply with the expression of variegate porphyria during its quiescent and acute phases.     

Effect of simvastatin therapy on blood and tissue ATP levels and erythrocyte membrane lipid composition

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors decrease mevalonate and subsequently cholesterol synthesis competitively. Mevalonate is also the precursor of ubiquinone. Ubiquinone is an important component of electron transport chain. We therefore investigated the effect of simvastatin on rat blood and tissue ATP concentrations and the lipid composition of red blood cell membranes after 4 weeks of therapy. Significant reductions in rat plasma cholesterol, triglyceride, and blood ATP concentrations were detected. Tissue ATP levels were not affected. Membrane phospholipids increased, while cholesterol and the cholesterol to phospholipid ratio decreased (P<0.05). A positive correlation between the plasma cholesterol concentration and the cholesterol to phospholipid ratio was noted (P<0.05, r=0.851). Our results show that HMG-CoA reductase inhibitors change the composition and probably also the functions of cell membrane lipids and blood ATP concentration.     

Erythrocyte uroporphyrinogen-I-synthase activity in β-thalassaemic patients

Abstract. The haem pathway enzyme uroporphyrino-gen-I-synthase (UPGS) was assayed in erythrocyte samples from twenty normal, twenty β-thalassaemia heterozygotic and twenty jS-thalassaemia homozygotic subjects, after partial separation of the erythrocytes according to their age. UPGS erythrocyte enzyme concentration activity was significantly higher in the young than in the old erythrocytes of normal (66·5 ± 11·8 v. 45 ± 9·5 nmol h^-1 I^-1, mean ± SD, P < 0·001) and β-thalassaemia heterozygotic subjects (70·1 ± 18·7 v. 49·8 ± 14·5 nmol h^-1 I^-1, P lt; 0·001), but not in patients with homozygous β-thalassaemia (46·0 ± 12·8 v. 44·1 ± 12·5 nmol h^-1 I^-1, P = 0·65). Furthermore, UPGS enzyme concentration of both young and old erythrocytes of homozygous β-thalassaemia was significantly lower than that of the young ( P < 0·001) but similar to that of the old ( P > 0·2) erythrocytes of either normal or β-thalassaemia heterozygotic subjects. Since severe chronic haemolysis due to haemoglobinopathies is associated with increased UPGS enzyme concentration, these results suggest that UPGS activity may be suppressed in homozygous β-thalassaemia.     

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis

The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.     

Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.

BACKGROUND: Grapefruit juice greatly increases the bioavailability of lovastatin and simvastatin. We studied the effect of grapefruit juice on the pharmacokinetics of atorvastatin and pravastatin. METHODS: Two randomized, two-phase crossover studies were performed--study I with atorvastatin in 12 healthy volunteers and study II with pravastatin in 11 healthy volunteers. In both studies, volunteers took 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested a single 40 mg dose of atorvastatin (study I) or pravastatin (study II) with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours later. In addition, subjects took 200 mL grapefruit juice or water three times a day on days 4 and 5 in study I. In study I, serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid, 2-hydroxyatorvastatin lactone, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 72 hours. In study II, pravastatin, pravastatin lactone, and active and total HMG-CoA reductase inhibitors were measured up to 24 hours. RESULTS: Grapefruit juice increased the area under the serum concentration-time curve of atorvastatin acid from time zero to 72 hours [AUC(0-72)] 2.5-fold (P < .01), whereas the peak serum concentration (Cmax) was not significantly changed. The time of the peak concentration (tmax) and the elimination half-life (t1/2) of atorvastatin acid were increased (P < .01). The AUC(0-72) of atorvastatin lactone was increased 3.3-fold (P < .01) and the Cmax 2.6-fold (P < .01) by grapefruit juice, and the tmax and t1/2 were also increased (P < .05). Grapefruit juice decreased the Cmax (P < .001) and AUC(0-72) (P < .001) of 2-hydroxyatorvastatin acid and increased its tmax and t1/2 (P < .01). Grapefruit juice also decreased the Cmax (P < .001) and AUC(O-72) (P < .05) of 2-hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.3-fold (P < .05) and 1.5-fold (P < .01), respectively, by grapefruit juice. In study II, the only significant change observed in the pharmacokinetics of pravastatin was prolongation of the tmax of active HMG-CoA reductase inhibitors by grapefruit juice (P < .05). CONCLUSIONS: Grapefruit juice significantly increased serum concentrations of atorvastatin acid, atorvastatin lactone, and active and total HMG-CoA reductase inhibitors, probably by decreasing CYP3A4-mediated first-pass metabolism of atorvastatin in the small intestine. On the other hand, grapefruit juice had no effect on the pharmacokinetics of pravastatin. Concomitant use of atorvastatin and at least large amounts of grapefruit juice should be avoided, or the dose of atorvastatin should be reduced accordingly.     

A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers

Abstract. The metabolic and cardiovascular effects of recombinant human IGF-I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6-²H₂]glucose (0–480 min) and in random order either IGF-I 20μg kg^-1 h^-1 (43.7 pmol kg^-1 min^-1) or insulin 0.5 mU kg^-1 min^-1 (3.4 pmol kg^-1 min^-1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF-I infusion glucose appearance rate (Ra) decreased from 1.79 ± 0.13 at baseline (150–180 min) to 0.35 ± 0.26 mg kg^-1 min^-1 ( P < 0.01) at 360min, and glucose utilization rate (Rd) increased from 1.79 ± 0.28 to 4.17 ± 0.84 mg kg^-1 min^-1 ( P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre-infusion mean) in cardiac output + 37.3%± 9% ( P < 0.01), heart rate + 13%± 2% ( P < 0.01) and stroke volume + 21%± 7% ( P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 ± 0.13 to 0.34 ± 0.33 mg kg^-1 min^-1 ( P < 0.01) and FFA from 0.546 mmoll^-1 to 0.198 mmoll^-1 ( P < 0.01), glucose Rd increased from l.89 ± 0.18 to 5.41 ± l.47mg kg^-1 min^-1 ( P < 0.01) and there were no significant changes in the cardiovascular variables.     

Heterozygous familial hypercholesterolaemia is associated with pathological exercise-induced leakage of muscle proteins, which is not aggravated by simvastatin therapy

Abstract. The objective of this study was to assess the relationship between therapy with the HMG-CoA reductase inhibitor simvastatin and muscle damage and the possible causal role of hypercholesterolaemia. The exercise-induced release of muscle proteins as a parameter of muscle damage was studied in two equicholesterolaemic groups of male patients with heterozygous familial hypercholesterolaemia (FH); one group without treatment, the second group on simvastatin. To assess the role of cholesterol, a third group of healthy male volunteers was studied as well. The study took place at the Lipid Clinic of an 800-bed University Hospital. One group of 21 male patients with heterozygous FH did not receive treatment, except for a lipid-lowering diet. A second group of 13 male FH patients were treated with 40 mg simvastatin day^-1 for at least 1 year and matched for cholesterol levels with the first group. A third group consisted of 25 normocholesterolaemic male controls. All subjects underwent a 45 min lean body mass (LBM) standardized ergometer muscle provocation test (2 Watt/kg LBM). Levels of creatine kinase (CK) and myoglobin (Mb) were assessed before and 1 and 8 h after exercise and compared with baseline levels. The exercise-induced release of muscle proteins is reflected by peak CK and Mb levels expressed as a percentage of baseline levels. The exercise-induced increase in Mb and CK levels did not differ between untreated and simvastatin-treated FH patients. However, the increase in Mb 1 h after exercise in untreated FH patients (181% of baseline level) and in simvastatin-treated patients (144% of baseline level) differed significantly from controls (107% of baseline level, P < 0.025, Mann-Whitney test). We conclude that hypercholesterolaemia may be associated with muscle damage, and the CK rises observed under therapy with HMG-CoA reductase inhibitors might be attributed to hypercholesterolaemia per se .     

Direct determination of leucine metabolism and protein breakdown in humans using L-[1-13C, 15N]-leucine and the forearm model

Abstract. We have used the forearm model to study protein metabolism in six normal healthy subjects in the fed state using L-[1 –¹³C, ¹⁵N]-leucine as the substrate tracer.
Deep venous and arterialized venous blood samples from the forearm were collected at 10-min intervals 2±5 h into a primed-continuous infusion of the dilabelled tracer. Arterialized venous blood was obtained using a 'hot-box' technique and forearm blood flow was measured by mercury strain-gauge plethysmography.
The concentration and isotope enrichment of leucine and its metabolites, α-ketoisocaproic acid and CO₂, in deep venous and arterialized venous blood were measured by gas chromatography-mass spectrometry and isotope ratio-mass spectrometry.
The rates of leucine deamination and reamination were 388 ± 24 (mean ± SEM) and 330 ± 23 nmol (100 ml)^-1 min^-1 respectively, whilst protein synthesis and breakdown rates were 127 ± 11 and 87 ± 10 nmol (100 ml)^-1 min^-1 respectively across the forearm in the fed state. We have demonstrated that the use of doubly labelled leucine as tracer and application of the mathematical model developed in this study, permits the comprehensive quantification of leucine kinetics including protein breakdown.